Alzheimer's disease (AD), the most common cause of dementia in the elderly, is now the third major cause of death in the United States. AD is characterized and diagnosed by distinctive neuropathological alterations including extracellular deposits of the ?-amyloid (A?) peptide intraneuronal aggregates of the microtubule associated protein tau (MAPT) and marked neuroinflammation. However, the exact mechanistic relationship between neuroinflammation and the various brain pathologies and clinical outcomes in AD remains unclear as well as the respective roles of brain resident microglia and infiltrating peripheral immune cells in these processes. Recent genetic and system biology studies have implicated multiple innate immune signaling pathways in late-onset AD. Most importantly, rare heterozygous coding mutations in TREM2, a gene exclusively expressed by myeloid cells were identified that substantially increase risk for AD and other neurodegenerative diseases. Our preliminary findings demonstrate that TREM2 is upregulated in mouse models of AD with A? pathology and human AD. Furthermore, co-localization studies demonstrated that TREM2 is selectively upregulated within myeloid cells in close proximity to A? deposits, but not in myeloid cells further away from A? deposits. Strikingly, careful flow cytometry and immunohistochemical analyses of brains from mouse models of AD revealed that TREM2 is upregulated within cells that bear markers reflective of their potential origin from circulating inflammatory monocytes. Consistent with these findings, preliminary analysis revealed an increase in TREM2+ cells in human AD blood samples. Furthermore, TREM2 deficiency in an AD mouse model leads to a virtual absence of the myeloid cells surrounding A? deposits and an overall reduction in AD-like pathologies. Finally, nuclear receptor agonists selectively target these plaque-associated TREM2+ cells and promote phagocytosis. The hypothesis to be tested in the current collaborative and interdisciplinary studies is that brain resident microglia and blood-derived TREM2+ inflammatory monocytes play distinctive roles in regulating AD pathologies that could provide novel biomarkers/diagnostics and also be targeted therapeutically. These studies will utilize state-of-the art mouse models of AD, constitutive Trem2 knockout mice, transgenic mice enabling deletion of TREM2 in various myeloid cell populations, detailed flow cytometry and genome-wide gene expression analyses as well as neuropathology and behavior to examine the three Specific Aims of the proposal: 1. Examine the Identity, Localization and Gene Expression Profiles of TREM2+ Cells in Mouse Models and Human AD. 2. Determine the Central and Peripheral Role of TREM2 in Regulating AD Pathologies. 3. Therapeutically Targeting TREM2+ Cells.